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https://www.readbyqxmd.com/read/28856237/t-cell-activating-mesenchymal-stem-cells-as-a-biotherapeutic-for-hcc
#1
Arpad Szoor, Abishek Vaidya, Mireya Paulina Velasquez, Zhuyong Mei, Daniel L Galvan, David Torres, Adrian Gee, Andras Heczey, Stephen Gottschalk
The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3)(+) HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL)...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28855349/prognostic-role-of-epidermal-growth-factor-receptor-variant-iii-egfrviii-positivity-in-egfr-amplified-primary-and-recurrent-glioblastomas
#2
Joerg Felsberg, Bettina Hentschel, Kerstin Kaulich, Dorothee Gramatzki, Angela Zacher, Bastian Malzkorn, Marcel Alexander Kamp, Michael C Sabel, Matthias Simon, Manfred Westphal, Gabriele Schackert, Jörg-Christian Tonn, Torsten Pietsch, Andreas von Deimling, Markus Loeffler, Guido Reifenberger, Michael Weller
PURPOSE: Approximately 40% of all glioblastomas have amplified the epidermal growth factor receptor (EGFR) gene and about half of these tumors express the EGFRvIII variant. The prognostic role of EGFRvIII in EGFR-amplified glioblastoma patients and changes in EGFRvIII expression in recurrent versus primary glioblastomas remain controversial, but such data are highly relevant for EGFRvIII-targeted therapies. EXPERIMENTAL DESIGN: EGFR-amplified glioblastomas from 106 patients were assessed for EGFRvIII positivity...
August 29, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28844499/rindopepimut-with-temozolomide-for-patients-with-newly-diagnosed-egfrviii-expressing-glioblastoma-act-iv-a-randomised-double-blind-international-phase-3-trial
#3
Michael Weller, Nicholas Butowski, David D Tran, Lawrence D Recht, Michael Lim, Hal Hirte, Lynn Ashby, Laszlo Mechtler, Samuel A Goldlust, Fabio Iwamoto, Jan Drappatz, Donald M O'Rourke, Mark Wong, Mark G Hamilton, Gaetano Finocchiaro, James Perry, Wolfgang Wick, Jennifer Green, Yi He, Christopher D Turner, Michael J Yellin, Tibor Keler, Thomas A Davis, Roger Stupp, John H Sampson
BACKGROUND: Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. METHODS: In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries...
August 22, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28830458/role-of-mek-partner-1-in-cancer-stemness-through-mek-erk-pathway-in-cancerous-neural-stem-cells-expressing-egfrviii
#4
Soo-Jung Kwon, Ok-Seon Kwon, Keun-Tae Kim, Young-Hyun Go, Si-In Yu, Byeong-Ha Lee, Hiroyuki Miyoshi, Eunsel Oh, Seung-Ju Cho, Hyuk-Jin Cha
BACKGROUND: Glioma stem cells (GSCs) are a major cause of the frequent relapse observed in glioma, due to their high drug resistance and their differentiation potential. Therefore, understanding the molecular mechanisms governing the 'cancer stemness' of GSCs will be particularly important for improving the prognosis of glioma patients. METHODS: We previously established cancerous neural stem cells (CNSCs) from immortalized human neural stem cells (F3 cells), using the H-Ras oncogene...
August 22, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28797294/the-anti-vascular-endothelial-growth-factor-receptor-1-monoclonal-antibody-d16f7-inhibits-invasiveness-of-human-glioblastoma-and-glioblastoma-stem-cells
#5
Maria Grazia Atzori, Lucio Tentori, Federica Ruffini, Claudia Ceci, Lucia Lisi, Elena Bonanno, Manuel Scimeca, Eskil Eskilsson, Thomas Daubon, Hrvoje Miletic, Lucia Ricci Vitiani, Roberto Pallini, Pierluigi Navarra, Rolf Bjerkvig, Stefania D'Atri, Pedro Miguel Lacal, Grazia Graziani
BACKGROUND: Glioblastoma (GBM) is a highly migratory, invasive, and angiogenic brain tumor. Like vascular endothelial growth factor-A (VEGF-A), placental growth factor (PlGF) promotes GBM angiogenesis. VEGF-A is a ligand for both VEGF receptor-1 (VEGFR-1) and VEGFR-2, while PlGF interacts exclusively with VEGFR-1. We recently generated the novel anti-VEGFR-1 monoclonal antibody (mAb) D16F7 that diminishes VEGFR-1 homodimerization/activation without affecting VEGF-A and PlGF binding. METHODS: In the present study, we evaluated the expression of VEGFR-1 in human GBM tissue samples (n = 42) by immunohistochemistry, in cell lines (n = 6) and GBM stem cells (GSCs) (n = 18) by qRT-PCR and/or western blot analysis...
August 10, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28774835/current-and-emerging-biomarkers-in-tumors-of-the-central-nervous-system-possible-diagnostic-prognostic-and-therapeutic-applications
#6
REVIEW
Ishaq N Khan, Najeeb Ullah, Deema Hussein, Kulvinder S Saini
Recent investments in research associated with the discovery of specific tumor biomarkers important for efficient diagnosis and prognosis are beginning to bear fruit. Key biomarkers could potentially outweigh traditional radiological or pathological methods by enabling specificity of early detection, when coupled with tumor molecular profiling and clinical associations. Only few biomarkers are approved by regulatory authorities for Central Nervous System Tumors (CNSTs), despite the evaluation of a large number of CNST related markers during clinical trials...
July 31, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28768863/hras-egfr-met-and-ron-are-recurrently-activated-by-provirus-insertion-in-mav-2-retrovirus-induced-liver-tumors
#7
Vladimir Pecenka, Petr Pajer, Vít Karafiat, Petra Kasparova, Jana Dudlova, Michal Dvorak
Myeloblastosis-associated virus-2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infected in ovo with MAV-2 develop tumors in kidneys, lungs, and liver with a short latency of less then 8 weeks. Here we report the results of molecular analyses of MAV-2-induced liver tumors that fall into three classes: hepatic hemangiosarcomas (HHS), intrahepatic cholangiocarcinomas (ICC), and hepatocellular carcinomas (HCC). Comprehensive inverse PCR-based screening of 92 chicken liver tumors revealed that in ca 86 % of these tumors, MAV-2 provirus had integrated into one of four gene loci: HRAS, EGFR, MET, and RON Insertionally mutated genes correlated with tumor type - HRAS was hit in HHSs, MET in ICCs, RON mostly in ICCs and EGFR mostly in HCC...
August 2, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28766870/extracellular-hyaluronic-acid-influences-the-efficacy-of-egfr-tyrosine-kinase-inhibitors-in-a-biomaterial-model-of-glioblastoma
#8
Sara Pedron, Jacob S Hanselman, Mark A Schroeder, Jann N Sarkaria, Brendan A C Harley
3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients...
August 2, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28765159/the-power-of-the-few
#9
REVIEW
Ran Chen, Yuan Pan, David H Gutmann
Converging evidence from numerous laboratories has revealed that malignant brain cancers are complex ecological systems composed of distinct cellular and acellular elements that collectively dictate glioblastoma biology. Our understanding of the individual contributions of each of these components is vital to the design of effective therapies against these cancers. In this issue of Genes & Development, Zanca and colleagues (pp. 1212-1227) demonstrate that one subpopulation of glioblastoma cells expressing a mutant epidermal growth factor receptor (EGFRvIII) is responsible for the survival of non-EGFRvIII-expressing tumor cells as well as for evading molecularly targeted therapy...
June 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28758103/circulating-micrornas-as-emerging-non-invasive-biomarkers-for-gliomas
#10
REVIEW
Alessandra Santangelo, Anna Tamanini, Giulio Cabrini, Maria Cristina Dechecchi
No single circulating biomarker has been put to practice for malignant gliomas so far, the most lethal primary brain tumors. Many promising protein biomarkers such as the mutant EGFRvIII or glial fibrillary acidic protein (GFAP) have already been detected in the blood and cerebrospinal fluid (CSF) of patients with gliomas, but their clinical value is still pending validation. Furthermore, these and other proteins seem to lack sufficient sensitivity and specificity required for a successful biomarker in this clinical setting...
July 2017: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28729770/enumeration-and-molecular-characterization-of-circulating-tumor-cell-using-an-in-vivo-capture-system-in-squamous-cell-carcinoma-of-head-and-neck
#11
Haidong Zhang, Shanchun Gong, Yaqun Liu, Longjun Liang, Shuangba He, Qingxiang Zhang, Mingyuan Si, Zhenkun Yu
OBJECTIVE: Detection rate and isolation yield of circulating tumor cell (CTC) are low in squamous cell carcinoma of head and neck (SCCHN) with in vitro approaches due to limited sample volumes. In this study, we applied the CellCollector to capture CTC in vivo from peripheral blood. METHODS: In total, the study included 22 cases with 37 times of detection. All of the patients were newly diagnosed with locally advanced or metastatic SCCHN, including laryngocarcinoma (40...
June 2017: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
https://www.readbyqxmd.com/read/28724615/glioblastoma-cellular-cross-talk-converges-on-nf-%C3%AE%C2%BAb-to-attenuate-egfr-inhibitor-sensitivity
#12
Ciro Zanca, Genaro R Villa, Jorge A Benitez, Amy Haseley Thorne, Tomoyuki Koga, Matteo D'Antonio, Shiro Ikegami, Jianhui Ma, Antonia D Boyer, Afsheen Banisadr, Nathan M Jameson, Alison D Parisian, Olesja V Eliseeva, Gabriela F Barnabe, Feng Liu, Sihan Wu, Huijun Yang, Jill Wykosky, Kelly A Frazer, Vladislav V Verkhusha, Maria G Isaguliants, William A Weiss, Timothy C Gahman, Andrew K Shiau, Clark C Chen, Paul S Mischel, Webster K Cavenee, Frank B Furnari
In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs)...
July 19, 2017: Genes & Development
https://www.readbyqxmd.com/read/28724573/a-single-dose-of-peripherally-infused-egfrviii-directed-car-t-cells-mediates-antigen-loss-and-induces-adaptive-resistance-in-patients-with-recurrent-glioblastoma
#13
Donald M O'Rourke, MacLean P Nasrallah, Arati Desai, Jan J Melenhorst, Keith Mansfield, Jennifer J D Morrissette, Maria Martinez-Lage, Steven Brem, Eileen Maloney, Angela Shen, Randi Isaacs, Suyash Mohan, Gabriela Plesa, Simon F Lacey, Jean-Marc Navenot, Zhaohui Zheng, Bruce L Levine, Hideho Okada, Carl H June, Jennifer L Brogdon, Marcela V Maus
We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up...
July 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28685576/egfr-egfrviii-dual-targeting-peptide-mediated-drug-delivery-for-enhanced-glioma-therapy
#14
Jiani Mao, Danni Ran, Cao Xie, Qing Shen, Songli Wang, Weiyue Lu
Tumor-homing peptides have been widely used to mediate active targeted drug delivery. l-AE is a reported targeting peptide demonstrating high binding affinity to epidermal growth factor receptor (EGFR) and mutation variant III (EGFRvIII) overexpressed on neovasculature, vasculogenic mimicry, tumor cells, and tumor stem cells. To improve its proteolytic stability, a d-peptide ligand (termed d-AE, the enantiomer of l-AE) was developed. d-AE was confirmed to bind receptors EGFR and EGFRvIII with targeting capability comparable to l-AE...
July 17, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28679777/efficacy-of-onalespib-a-long-acting-second-generation-hsp90-inhibitor-as-a-single-agent-and-in-combination-with-temozolomide-against-malignant-gliomas
#15
Alessandro Canella, Alessandra M Welker, Ji Young Yoo, Jihong Xu, Fazly S Abbas, Divya Kesanakurti, Prabhakaran Nagarajan, Christine E Beattie, Erik P Sulman, Joseph L Liu, Joy Gumin, Frederick F Lang, Metin Gurcan, Balveen Kaur, Deepa Sampath, Vinay K Puduvalli
HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities or are unable to cross the blood brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas invitro and invivo<br /><br />Experimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined...
July 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28663030/early-experience-with-formalin-fixed-paraffin-embedded-ffpe-based-commercial-clinical-genomic-profiling-of-gliomas-robust-and-informative-with-caveats
#16
Masoud Movassaghi, Maryam Shabihkhani, Seyed A Hojat, Ryan R Williams, Lawrance K Chung, Kyuseok Im, Gregory M Lucey, Bowen Wei, Sergey Mareninov, Michael W Wang, Denise W Ng, Randy S Tashjian, Shino Magaki, Mari Perez-Rosendahl, Isaac Yang, Negar Khanlou, Harry V Vinters, Linda M Liau, Phioanh L Nghiemphu, Albert Lai, Timothy F Cloughesy, William H Yong
BACKGROUND: Commercial targeted genomic profiling with next generation sequencing using formalin-fixed paraffin embedded (FFPE) tissue has recently entered into clinical use for diagnosis and for the guiding of therapy. However, there is limited independent data regarding the accuracy or robustness of commercial genomic profiling in gliomas. METHODS: As part of patient care, FFPE samples of gliomas from 71 patients were submitted for targeted genomic profiling to one commonly used commercial vendor, Foundation Medicine...
August 2017: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/28649003/targeting-egfrviii-for-glioblastoma-multiforme
#17
Ju Yang, Jing Yan, Baorui Liu
Glioblastoma multiforme (GBM) is the most progressive primary brain tumor. Targeting a novel and highly specific tumor antigen is one of the strategies to overcome tumors. EGFR variant III (EGFRvIII) is present in 25%-33% of all patients with GBM and is exclusively expressed on tumor tissue cells. Currently, there are various approaches to target EGFRvIII, including CAR T-cell therapy, therapeutic vaccines, antibodies, and Bi-specific T Cell Engager. In this review, we focus on the preclinical and clinical findings of targeting EGFRvIII for GBM...
June 23, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28634045/egfr-egfrviii-remodels-the-cytoskeleton-via-epigenetic-silencing-of-ajap1-in-glioma-cells
#18
Chao Yang, Yan-Sheng Li, Qi-Xue Wang, Kai Huang, Jian-Wei Wei, Yun-Fei Wang, Jun-Hu Zhou, Kai-Kai Yi, Kai-Liang Zhang, Bing-Cong Zhou, Cong Liu, Liang Zeng, Chun-Sheng Kang
EGFR amplification and mutations are the most common oncogenic events in GBM. EGFR overexpression correlates with GBM invasion, but the underlying mechanisms are poorly understood. In a previous study, we showed that AJAP1 is involved in regulating F-actin to inhibit the invasive ability of GBM. In addition, in a GBM cell line, the AJAP1 promoter was highly bound by H3K27me3 and, through bioinformatics analysis, we found that AJAP1 expression was negatively correlated with EGFR. In this study, we found that the pathway downstream of EGFR had a higher activation level in GBM cell lines, which led to excessive tumor suppressor silencing...
June 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28631186/association-between-epidermal-growth-factor-receptor-amplification-and-adp-ribosylation-factor-1-methylation-in-human-glioblastoma
#19
Concha López-Ginés, Lara Navarro, Lisandra Muñoz-Hidalgo, Enrique Buso, José Manuel Morales, Rosario Gil-Benso, Mariela Gregori-Romero, Javier Megías, Pedro Roldán, Remedios Segura-Sabater, José Manuel Almerich-Silla, Daniel Monleón, Miguel Cerdá-Nicolás
PURPOSE: Glioblastoma (GB) is the most frequent and most malignant primary brain tumor in adults. Previously, it has been found that both genetic and epigenetic factors may play critical roles in its etiology and prognosis. In addition, it has been found that the epidermal growth factor receptor gene (EGFR) is frequently over-expressed and amplified in primary GBs. Here, we assessed the promoter methylation status of 10 genes relevant to GB and explored associations between these findings and the EGFR gene amplification status...
August 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28629170/egfr-and-egfrviii-promote-angiogenesis-and-cell-invasion-in-glioblastoma-combination-therapies-for-an-effective-treatment
#20
REVIEW
Stefanie Keller, Mirko H H Schmidt
Epidermal growth factor receptor (EGFR) and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM), the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related angiogenesis and their upregulation correlates with the poor prognosis of glioma patients. Glioma cell invasion and increased angiogenesis share mechanisms of the degradation of the extracellular matrix (ECM) through upregulation of ECM-degrading proteases as well as the activation of aberrant signaling pathways...
June 18, 2017: International Journal of Molecular Sciences
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